Synthesis of Optically Pure Cyclometalated Iridium(III) Complex-Peptide Hybrids and Their Anticancer Activity

We report on the synthesis of optically pure cyclometalated iridium(III) complex-peptide hybrids as amphiphilic peptide conjugates (IPH-ACs) and the effect of the stereochemistry with respect to their Ir(tpy)₃ (tpy: 2-(4′-tolyl)pyridine) core on their cytotoxicity against cancer cells. Stereochemically pure IPH-ACs were synthesized from Δ- and Λ-Ir(tpyCO₂H)₃ by optical resolution via the diastereomeric intermediates that are conjugated with the chiral alcohol, (1R,2R)-2-aminocyclohexanol ((R,R)-11), followed by the hydrolysis of the ester moieties, as we reported very recently, and their spectroscopic spectra are reported. It was found that both optically pure Δ- and Λ-forms of IPH-ACs induce paraptotic cell death in Jurkat cells and the EC₅₀ values were evaluated by MTT assays. We also performed TEM (transmission electron microscope) analyses of Jurkat cells treated with Λ-13 to observe morphological changes in paraptosis processes. The intracellular uptake of Λ-forms of IPH-ACs in the cells measured by ICP-MS (inductively coupled plasma-mass spectrometry) was higher than those of Δ-forms and the EC₅₀ values of the Λ-forms were smaller than those of the Δ-IPH-ACs. The analysis of these results suggests that the intrinsic cytotoxicity is almost equal for the Δ- and Λ-forms and that the difference in cytotoxicity against Jurkat cells is due to the selectivity in the intracellular uptake of each stereoisomer.